Structural and functional analysis of human pannexin 2 channel

  • Nat Commun. 2023 Mar 27;14(1):1712. doi: 10.1038/s41467-023-37413-z.
Zhihui He  #  1  2 ,  Yonghui Zhao  #  3  4 ,  Michael J Rau  5 ,  James A J Fitzpatrick  1  5  6  7 ,  Rajan Sah  2  8 ,  Hongzhen Hu  9  10 ,  Peng Yuan  11  12  13  14
Affiliations
  • 1. Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO, USA.
  • 2. Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, Saint Louis, MO, USA.
  • 3. Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA.
  • 4. Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, Saint Louis, MO, USA.
  • 5. Washington University Center for Cellular Imaging, Washington University School of Medicine, Saint Louis, MO, USA.
  • 6. Department of Neuroscience, Washington University School of Medicine, Saint Louis, MO, USA.
  • 7. Department of Biomedical Engineering, Washington University in Saint Louis, Saint Louis, MO, USA.
  • 8. Department of Internal Medicine, Cardiovascular Division, Washington University School of Medicine, Saint Louis, MO, USA.
  • 9. Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA. [email protected].
  • 10. Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, Saint Louis, MO, USA. [email protected].
  • 11. Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO, USA. [email protected].
  • 12. Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, Saint Louis, MO, USA. [email protected].
  • 13. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
  • 14. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
  • # Contributed equally.
PMID: 36973289 DOI: 10.1038/s41467-023-37413-z
Abstract

The pannexin 2 channel (PANX2) participates in multiple physiological processes including skin homeostasis, neuronal development, and ischemia-induced brain injury. However, the molecular basis of PANX2 channel function remains largely unknown. Here, we present a cryo-electron microscopy structure of human PANX2, which reveals pore properties contrasting with those of the intensely studied paralog PANX1. The extracellular selectivity filter, defined by a ring of basic residues, more closely resembles that of the distantly related volume-regulated anion channel (VRAC) LRRC8A, rather than PANX1. Furthermore, we show that PANX2 displays a similar anion permeability sequence as VRAC, and that PANX2 channel activity is inhibited by a commonly used VRAC inhibitor, DCPIB. Thus, the shared channel properties between PANX2 and VRAC may complicate dissection of their cellular functions through pharmacological manipulation. Collectively, our structural and functional analysis provides a framework for development of PANX2-specific reagents that are needed for better understanding of channel physiology and pathophysiology.